Impact of locus coeruleus-derived tau pathology in a rodent model of early Alzheimer's disease

蓝斑源性 tau 蛋白病理学对早期阿尔茨海默病啮齿动物模型的影响

基本信息

批准号：
10579830
负责人：
Shella D Keilholz
金额：
$ 46.1万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579830
关键词：
Affect Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Animals Anti-Inflammatory Agents Anxiety Disorders Area Arousal Attention Behavior Behavioral Paradigm Brain Brain region Cell Nucleus Clinical Trials Cognition Cognitive Data Dementia Depressed mood Diagnostic Disease model Early treatment Elderly Electrophysiology (science)Faculty Functional Magnetic Resonance Imaging Functional disorder Goals Healthcare Systems Hippocampus Human Human Amyloid Precursor Protein Hyperactivity Impaired cognition Inflammation Intervention Learning Lesion Mediating Memory impairment Mental Depression Morphology Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Norepinephrine Pathogenicity Pathologic Pathology Patients Pattern Performance Phenotype Property Prosencephalon Psyche structure Quality of life Rat Transgene Rattus Research Research Personnel Rest Rodent Rodent Model Senile Plaques Severities Sleep Disorders Stimulus Symptoms Testing Therapeutic Time Transgenes Transgenic Mice Viral Viral Vector biological adaptation to stress cognitive process entorhinal cortex experimental study extracellular frontal lobe imaging study in vivo innovation interest locus ceruleus structure loved ones mutant neurobehavioral neuroinflammation neuron loss neuropathology neuroprotection neuropsychiatry neurotoxicity noradrenergic norepinephrine system novel novel therapeutic intervention optogenetics presenilin-1 prevent prodromal Alzheimer&apos s disease promoter stressor targeted treatment tau Proteins tau aggregation tau mutation therapeutic target tool transmission process

项目摘要

Amyloid-β (Aβ) plaques and tau neurofibrillary tangles, as well as neuronal death, are the pathologic hallmarks of Alzheimer's disease (AD). Therapeutic efforts focused on Aβ have thus far failed, underscoring the urgent need for alternate approaches, particularly those that can target early AD. Aberrant tau in the locus coeruleus (LC), the major noradrenergic nucleus in the brain that regulates attention, arousal, stress responses, and cognition, is the earliest detectable AD-like neuropathology in the human brain, and LC degeneration is ubiquitious in later AD. Recent research indicates that early LC dysfunction may contribute to prodromal AD symptoms such as depression, anxiety, and sleep disorders, while later LC degeneration exacerbates cognitive impairment. Although these data suggest that the LC is a promising therapeutic target in AD, almost nothing known about how pathogenic tau impacts LC function and survival. We have developed a viral vector that drives the expression of wild-type human tau exclusively in LC neurons, which over time becomes hyperphosphorylated and misfolded, thus recapitulating the earliest forms of human AD. We will use this novel tool to study the consequences tau pathology in the LC. In Aim 1, we will determine the impact of different forms of aberrant tau on LC neuron morphology, survival, and local inflammation, and assess the potential of LC-derived tau pathology to spread to interconnected forebrain regions. In Aim 2, we will use in vivo electrophysiology and behavioral paradigms to evaluate how tau pathology affects LC activity and performance in neuropsychiatric and cognitive domains. In Aim 3, we will combine optogenetics and fMRI to determine how aberrant tau influences LC-forebrain functional connectivity. Completion of these aims will lay the groundwork for LC/tau-based therapies for early AD.

淀粉样蛋白β（Aβ）斑块和Tau神经原纤维缠结以及神经元死亡是病理标志阿尔茨海默氏病（AD）。迄今为止，重点关注Aβ的治疗努力失败了，强调了紧急需要替代方法，尤其是那些可以针对早期广告的方法。位点层中的异常tau （LC），大脑中主要的去甲肾上腺素能，可调节注意力，唤醒，应力反应和认知，是人脑中最早可检测到的广告状神经病理学，LC变性为在以后的广告中无处不在。最近的研究表明，早期的LC功能障碍可能导致前驱AD 抑郁症，焦虑和睡眠障碍等症状，而后来的LC退化加剧了认知损害。尽管这些数据表明LC是AD中有前途的治疗靶点，但几乎没有知道致病性TAU如何影响LC功能和生存。我们已经开发了一个病毒载体在LC神经元中驱动野生型人tau的表达，随着时间的流逝过度磷酸化和错误折叠，从而概括了人类AD的最早形式。我们将使用这本小说研究LC中TAU病理的后果的工具。在AIM 1中，我们将确定不同的影响 LC神经元形态，生存和局部炎症的异常TAU形式，并评估 LC衍生的TAU病理传播到相互联系的前脑区域。在AIM 2中，我们将使用体内电生理学和行为范例，以评估tau病理如何影响LC活性和性能在神经精神病学和认知领域。在AIM 3中，我们将结合光遗传学和fMRI，以确定如何异常TAU影响LC - 外交功能连接性。这些目标的完成将奠定基础用于早期AD的基于LC/TAU的疗法。